Sex Differences in Ependymoma Methylation by Methylation-Defined Subgroup

Ependymoma is the second most common malignant paediatric brain tumour composed of nine methylation-defined, clinically relevant subgroups. It is unclear if there are sex differences in methylation profiles within these subgroups which could guide future treatment options. We obtained available methylation data from the National Center for Biotechnology Information Gene Expression Omnibus (GEO). Differentially methylated probes (DMPs) between sexes were identified in each ependymoma sample and mapped to genes. Reactome pathways resulting from genes were identified. Survival was estimated for each sex within molecular subgroups. There were 492 cases included in the main analysis: PF-EPN-A (n = 238) PF-EPN-B (n = 52), PF-SE (n = 34), SP-MPE (n = 26), SP-EPN (n = 21), ST-EPN-RELA (n = 87), ST-EPN-YAP1 (n = 13) and ST-SE (n = 21). Females were observed to have better, but statistically nonsignificant, 5-year overall survival (OS) and better, marginally significant 5-year progression-free survival (PFS) than males. One subgroup, ST-EPN-RELA, showed significantly better OS in females. There was a difference in immune cell composition within tumour subgroups. One gene, RFTN1, was consistently differentially methylated by sex among all subgroups. There were biologic pathways identified from genes with differential methylation by sex in the following subgroups: PF-EPN-B, PF-SE, ST-EPN-RELA and ST-EPN-YAP1. Many of the identified pathways may be options for potential therapeutic targets.